PB2221: AN OPEN-LABEL, PHASE 1/1B STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, PHARMACODYNAMICS AND CLINICAL ACTIVITY OF IMETELSTAT IN COMBINATION WITH RUXOLITINIB IN PATIENTS WITH MYELOFIBROSIS: IMPROVEMF
Authors: Andrew Kuykendall, Terrence Bradley, Rami S. Komrokji, Tymara Berry, Souria Dougherty, Laurie Sherman, Lixian Peng, Fei Huang, Ying Wan, Vivian Rodolf, Judy Ho, Shyamala Navada, John Mascarenhas
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm. Janus kinase inhibitors (JAKis) can reduce splenomegaly and debilitating MF-related constitutional symptoms; however, they do not eliminate malignant clonal stem cells that drive disease progression and have limited activity on disease-altering effects. JAKi combination strategies are being explored as potential ways to improve response in MF. Imetelstat is a 13-mer lipid-conjugated oligonucleotide and a potent, first-in-class direct and competitive inhibitor of telomerase activity. Imetelstat has shown meaningful clinical improvement in symptom response and overall survival (OS) in the phase 2 IMbark study in patients (pts) with intermediate-2 (Int-2) or high-risk (HR) MF who are relapsed/refractory to JAKis. Imetelstat also demonstrated disease-modifying activity by targeting malignant clones, improving bone marrow fibrosis, and increasing OS. Studies in mice with MF pt-derived xenografts demonstrated that treatment with ruxolitinib (JAK1/JAK2 inhibitor) followed by imetelstat resulted in greater disease reduction than observed with either agent alone, while sparing normal hematopoiesis. Combining ruxolitinib and imetelstat may improve disease symptoms and may alter the natural history of MF through activity on malignant clonal stem cells. Aims: Part 1: Determine the recommended Part 2 dose (RP2D) of imetelstat in combination with ruxolitinib in pts with MF. Part 2: Evaluate safety and preliminary clinical activity of combination imetelstat with ruxolitinib in pts with MF. Methods: IMproveMF (MYF1001, NCT05371964) is an open-label, single-arm, multicenter, phase 1/1b study to evaluate the safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity of imetelstat in combination with ruxolitinib in pts with intermediate-1, Int-2, or HR MF (Figure). The Part 1 (phase 1) dose-escalation portion will use Bayesian optimal interval design to investigate 4 dose levels of imetelstat to identify the RP2D in combination with ruxolitinib. Three pts will be enrolled at each imetelstat dose level in a stepwise manner (maximum ≈21 pts). To allow each pt to reach an individualized stable dose of ruxolitinib and mitigate the risk of thrombocytopenia observed upon initiation of both ruxolitinib and imetelstat, single-agent ruxolitinib treatment is required for ≥12 weeks (maximum 24 weeks). In the Part 2 (phase 1b) dose confirmation and expansion portion, ≈20 pts will undergo open-label, single-arm combination treatment of ruxolitinib followed by imetelstat at the RP2D. Eligible pts will have an Eastern Cooperative Oncology Group Performance Status score of 0–2 and peripheral blood and marrow blast counts <10%. Pts cannot have clinically significant cardiovascular disease, active systemic hepatitis infection, chronic liver disease unrelated to underlying MF, or a prior history of a hematopoietic stem cell transplant or splenectomy. Results: Primary endpoints are incidence, type, and severity of adverse events (AEs, Part 1); and incidence and severity of AEs and symptom response rate at Week 24 (Part 2). Secondary endpoints include symptom response rate (Part 1 only) and spleen response rate at Week 24, progression-free survival, clinical response assessments per modified 2013 International Working Group – Myeloproliferative Neoplasms Research and Treatment criteria, time to and duration of response, reduction in bone marrow fibrosis, and the PK/immunogenicity of imetelstat. Summary/Conclusion: Phase 1 dose-escalation (Part 1) is open for enrollment at ≈3 sites across North America, targeting ≈41 pts.Keywords: Telomerase activity, Myelofibrosis, Janus Kinase inhibitor, Therapy